Cerebrovascular disease is the second leading cause of death in developed countries and accounts for high rates of disability. Current therapies for ischemic stroke [tissue plasminogen activator (tPA)] fail to benefit many victims due to the constraints of time to intervention, the significant incidence of treatment-associated hemorrhage, and the limited therapeutic effect of thrombolysis. Our long-term goal is to improve public health by developing ischemic stroke treatment approaches that overcome the limitations of current treatments. Guidelines for treatment currently focus on either (a) intravenous thrombolytic therapy within 3 hours of stroke onset or (b) intra-arterial mechanical intervention/thrombolysis within 6 hours. It has been recently shown in animal models that thrombolytic therapy may be enhanced by the addition of ultrasound. Furthermore, we hypothesize that combining ultrasound with intravenously injected microbubbles may facilitate mechanical disruption of thrombi in intracranial circulation without resulting in treatment-associated hemorrhage. We propose a pilot study that uses a rabbit model of acute embolic stroke to compare the utility of an intervention consisting of either 1] tPA treatment alone, 2] intravenously injected microbubbles with trans-cranial ultrasound, or 3] tPA treatment combined with microbubbles and ultrasound. We will explore the safety and efficacy of these various treatments for lysing three types of clots: fresh clots that simulate secondary clots associated with acute emboli during the window of therapeutic opportunity in ischemic stroke (Specific Aim 1), aged clots that are more typical of embolic clots that may not be fresh (Specific Aim 2), and insoluble embolic material more typical of atheromata (Specific Aim 3). Our ultimate objective for this pilot study is to test the refinement of novel treatments for embolic stroke that would yield a safe, simple, fast and successful therapy that can be further examined in future funded research projects and eventually applied in the clinical realm. Our proposed pilot study will determine which of these treatments is most successful, and future studies will further explore that treatment. (End of Abstract)